3, 5-diketo-pyrazolidines



United States Patent 3,5-DlKETO-PYRAZOLIDINES Ernst Jucker and Arnold Vogel, Binningen, and Erwin Rissi, Basel, Switzerland, assignors to Sandoz A. G.,

Basel, Switzerland, a Swiss firm No Drawing. Application January 2,1957

Serial No. 632,022

Claims priority, application Switzerland January 7, 1956 Claims. (Cl. 260294.7)

- The present invention provides new and therapeutically valuable 3,5-diketo-pyrazolidine derivatives.

The 3,5-diketo-pyrazolidine derivatives according to the present invention correspond to the formula wherein each of R and R is an ali alkyl such as methyl, ethyl, n-butyl, e

phatic group (e. g. to.) or an aromatic group (e. g. phenyl, substituted phenyl, benzyl, etc.), R

to 4 carbon atoms (e. g. methyl,

wherein R and R have the precedingly-indicated significances with a reactive derivative of malonic acid, which derivative corresponds to the formula R2/ \OOX wherein R and R also have their p (III) recedingly-indicated significances, and X is Br, Cl, N O-alkyl or NH;,,. Thus,

:for example, to a solution of diphenyl-malonyl dichloride in an inert solvent such as tetrahydrofurane or chloroform, there is added at room temperature (about 20 to about 30 C.) first a solution of compound II, e. g. N-

amine may be dispensed with, if desired.

The piperidyl-4-hydrazines can als number of ways,

o be prepared in a illustrative examples which follow. For example, an N- alkyl-4-piperidone of the formula 2,865,922 Patented Dec. 23, 1958 wherein R is as precedingly defined can be condensed with an alkyl hydrazine of the formula wherein R also has its precedingly-indicated significance, to produce the corresponding N-alkyl-piperidyl-4-alkylhydrazone which, upon reduction with hydrogen, yields the corresponding w-(N-alkyl-piperidyl-4)-w'-alkyl-hydrazine. The N-alkyl-piperidyl-4-alkyl-hydrazone may be acylated prior to the reduction, and the desired hydrazine derivative obtained by splitting oif the acyl group by saponification. The condensation of an N-alkyl-4- piperidone (IV) with an acyl derivative of hydrazine itself produces the corresponding N-alkyl-4-piperidoneacyl derivative which, upon hydrogenation, yields the corresponding hydrazine derivative, from which the acyl group may also be saponified off. It is also possible to proceed by reacting an N-alkyl-4-halogen-piperidine with a hydrazine of Formula V.

The products obtained according to the present inven tion, i. e. the new 3,5-diketo-pyrazolidine derivatives are, at room temperature, solid crystalline bases which form stable physiologically tolerable salts with a wide variety tartrates, methane sulfonates, etc.

The new products of this invention possess pharmacodynamic properties which good solubility of their salts makes possible the preparation of highly-concentrated ampoule solutions.

The diketo-pyrazolidines of this invention are thus especially suitable for treating chronic rheumatism, chronpresently preferred representative embodiments of the invention. In these examples, the parts and percentages are by Weight unless is evaporated to dryness under reduced pressure, and the residue is recrystallized from benzene-ether, yielding the benzoylhydrazone of N-methyl-4-piperidone; melting point 146147.

under reflux for 4 hours in 250 parts by volume of aqueons hydrochloric acid of 23% strength, after which the is then heated on the water-bath until all oily substance is dissolved. Precipitated potassium chloride is filtered "dissolved 'in 20 parts by 05, and the filtrate is evaporated to dryness under reduced pressure. The so-obtained residue is dissolved in boiling tetrahydrofurane, the solution filtered and the f ltrate evaporated to dryness under reduced pressure, after which the obtained residue is fractionated in a high vacuum. The obtained N-methyl-piperidyl lhydrazine "boils at 66-70 under a pressure of 0.25-0.32 mm. Hg; in is a colorless crystalline substance.

A solution of 12.9, parts of the so-obtained N-methyl- .piperidyl-4'-hydrazine in 40 parts by volume of tetra- -hydrofurane andthen--20.2-parts of triethylamine are added dropwise-to a solution of 29.2 parts of diphenylmalonyl di-chloride in 100 parts by volume of tetrahydrofurane at room temperature (about 20 to about 30), the resultant mixture is diluted with 80parts by volume of chloroform and is then boiled under reflux for 3 hours while being stirred. Thereupon the solution is filtered and the filtratethen evaporated under reduced pressure. The residue is dissolved inmethylene chloride and the solution is washed twice with '2-normal aqueous sodium carbonate solution, dried over sodiumsulfate and then evaporated under reduced pressure. The resultant crystalline residue is fractionally recrystallized from ethanol, yielding pure l-(N-methyl-piperidyl-4')-4,4-diphenyl- 3,5-diketo-pyrazolidine, which has a-melting point of 258- 263".

Example 2 A solution of 5.22 parts of N-methyl piperidyl-4-hydrazine and 11.2 parts by volume of triethylamine in 50 parts by volume of tetrahydrofur'ane is added'dropwise to asolution of 7.96 parts of diethylmalonyl di-chloride in 150 parts by volume of tetrahydrofurane at room temperature. An additional- 11.2 parts by volume of triethylam'ine are then added,and the mixture stirred for 4 hours at room temperature. The salts which precipi- 'tate are then filtered off and the filtrate is evaporated to dryness underreduced pressure. The so-obtained residue is dissolved in 150 parts by volume of methylene chloride, and the resultant solution is washed twice with 2-nor'rnal aqueous sodium carbonate solution, dried over sodium sulfate and then evaporated under reduced pres- 'sure. The obtained oily residue is dissolved in 50 parts by volume of benzene, and the solution is poured onto a column of 235 parts'of aluminum oxide and then, using mixtures of ether and ethanol, first in the proportion of 9:1,Qthen 4:1, and finally 1:1, there is eluted a crystalline substance 1-(N-methyl-piperidyl-4')-3,S-diketo-4,4- diethyl-pyrazolidine-- which after three recrystallizations from acetone, melts at 188189.

Example 3 8.0 parts of methylhydrazine, dissolved in 10 parts by volume of absolute ethanol, are added dropwise to a solution of 19.2 parts of N-methyll-piperidone, the temperature being maintained at between and 30, if necessary with the aid of a mixture of ice and salt. The mixture is then heated to 60-65 for 40 minutes. After the addition of parts of benzene, the water which formed is azeotropic'ally distilled OE With the alcohol, and the solution evaporated at 80 under reduced pressure. The obtained residue is then distilled under reduced pressure. (N methyl-4-piperidone)-methyl-hydrazone'distils over at -98"-99 under a pressure of 11 mm. Hg.

10 parts of benzoyl chloride, dissolved in 25- parts by volume 'of chloroform, are added dropwise to a solution of 10.0 parts of (N-methyl-4-piperidoue)-methyl-hydrazone in'30 parts by volume of chloroform, the temperature -being maintained at a maximum of 10 bycooling with an ice-salt mixture. The solution is then allowed to stand -at roorn temperature(about-2040") for 12'hours, and is their evaporated. The so 'obtained resin'ou's residue is volume of water, :20 parts by vemmeotaqueous caustic soda solution of 10% strength are added, and the resultant solution I extracted with 'benzoic acid and is evaporated to dryness chloroform. The chloroform solution, dried over sodium sulfate, is evaporated, leaving behind a viscous yellow oil, which crystallizes when rubbed. The product(N- methyl 4 piperidone)-methyl-benzoyl-hydrazone-crystallizes from acetone in the form of parallelopipeds which melt at 9 6-103; boiling'p'oint is 145150/ 0.1 mm. Hg.

A solution"of-'4.0 parts of:(N-methyl-4 piperidone)- methyl-benzoylhydrazone in 70 parts by volume of gla cial acetic acid: is added to a slurry of 080 part 'of prehydrogenated'platinum oxide in 10 parts by volume of glacial acetic acid, and the mixture then hydrogenated at room temperature and'under atmospheric pressure, whereupon the quantity -of'hydrogen required for the C=N double bond will be taken up within 3 hours. The solution' is separated from the catalyst by filtration arid is then evaporated at 60 under'reduced pressure, the residue being then dissolved in 10 parts by volume of ice water. After the addition of 15 parts by volume of aqueous caustic soda solution of 20% strength and saturation-with sodium chloride, the resultant mixture is extractedwith chloroform. The chloroform extractis dried over sodium sulfate and is then evaporated. The so-obtained residue yields, upon distillation in a high vacuum, w-(N-methylpiperidyl-4)-w-methyl-benzoyl hydrazine (which boils at 145-150/0.3 mm. Hg), and which upon recrystallization from ether-petroleum ether is obtained in the form of platelets and needles which melt at 70-76.

However, in order to prepare the hydrazine derivative itself by splitting off the benzoyl group from the benzoyl derivative, it is not necessary to prepare the latter in the pure state, but the crude hydrogenation product obtained after the evaporation of the glacial acetic acid may be directly worked up further.

800 parts by volume of aqueous hydrochloric acid of 23% strength are added to the crude w-(N-rnethylpiperidyl-4)-w-methyl-benzoyl-hydrazine obtained from the hydrogenation of 55.5 parts of benzoyl-hydrazone after evaporating off the glacial acetic acid, and the mixture is boiled under reflux for 5 hours. The resultant solution, cooled to 5, is filtered from the precipitated at under a pressure of 12 mm. Hg. The residue, upon recrystallization from methanol-ether, yields w-(N-methyl-piperidyl-4)-w'-methyl-hydrazine dihydrochloride in the form of colorless fine needles which, after being dried over phosphorus pcntoxide at 50 in'a high vacuum, melt at 187-210" with evolution of hydrogen chloride. The dihydrochloridc, upon being treated with methanolic potassium hydroxide solution, yields the free w-(N-methylpiperidyl-4) -w'-methyl-hydrazine as a water-clear colorless liquid which boils at 60/0.3 mm. Hg; 1.4835.

A solution of 1.43 parts of the so-obtained w-(N-methylpiperidyl-4)-w-methyl-hydrazine in 15 parts by volume of tetrahydrofurane are added dropwise to a solution, preliminarily cooled to 0, of 2.93 parts of diphcnylmalonyl dichloride in 40 parts by volume of tetrah 'drofurane, with stirring and further cooling with ice. The obtained mixture is then boiled under reflux for 2 hours. After cooling, the reaction mixture is diluted with ether and then extracted three times with 2-normal aqueous hydrochloric acid. The hydrochloric acid aqueous layer is rendered alkaline with concentrated aqueous caustic soda solution, and then extracted three times with methylene chloride. The obtained organic layer is dried over sodium sulfate and is evaporated, leaving-as residue an oil. The latter isdissolved in benzene, and the obtained solution is chromatographed on parts of aluminum oxide. Upon development of the chromatogra'm with benzene, benzene-ether mixtures in the proportion-first of 4:1 and then of 1:1, and finally with ether alone, there is eluted the 1 -(N-methyl piperidyl-4)- 2-methyl-4,4-diphenyl-3,5-diketo-pyrazolidine*which,-upon recrystallization from ether petroleum ether, has a melting point of 112-113".

Example 4 l-(N methyl piperidyl 4) 2 methyl 4,4 di nbutyl-3,S-dikto-pyrazolidine is prepared, after the manner set forth in the preceding example, from 2.53 parts of di-n-butyl-malonyl-dichloride and 1.43 parts of w-(N- methyl-piperidyll)-w'-methyl-hydrazine in the presence of 2.8 parts by volume of triethylamine. The so-prepared l-(N methyl piperidyl- 4') 2 methyl 4,4 di nbutyl-3,S-diketo-pyrazolidine can not be crystallized, after the chromatography, but is obtained as an oily substance. By passing dry hydrogen chloride into a solution of the latter in absolute ethanol, the monohydrochloride of the base is obtained in the form of crystals which, upon recrystallization from acetone-ether, have a melting point of ZOO-202.

Example 5 A solution of 1.43 parts of w-(N-methyl-piperidyl-4)- w-methyl-hydrazine in 15 parts by volume of tetrahydroof tetrahydrofurane, after which the mixture is boiled under reflux for 4 hours with stirring. After being allowed to cool, the reaction mixture is diluted with ether and then is extracted 3 times with 2-normal hydrochloric pressure, The latter is disbenzene, and the solution Example 6 chlorrc acid aqueous layeris solution is dried over sodium sulfate and evaporated under reduced pressure, leaving behind an oily crude product, the solution of which in 50 parts by volume of benzene is then poured onto a. column of the 30-fold quantity of aluminum oxide. Benzene, as well as benzeneether mixtures, 4:1 and 1:1, elute the l-(N-methyl-piperidyl-4)-2-methyl-4,4-dimethyl 3,5 diketo pyrazolidine. The so-obtained free base is crystalline; however, it cannot be recrystallized.

' The corresponding hydrochloride is prepared by passing dry hydrogen chloride into an ethanolic solution of the free base,I concentrating the solution and then adding ether, whereupon the 1-(N-methyl-piperidyl-4') 2 methyl- 4,4rdimethyl-3,S-diketo-pyrazcblidine hydrochloride .,crys- )-w drazine (boiling point 49-54/0.3 mm. Hg,

tallizes out. After recrystallization from ethanol-ether, it melts at 261262 (decomposition).

Example 7 ethanol,

volume of ethanol, the temperature being maintained at -15 to 5 by cooling. The resultant mixture is then heated to 60-80 After the addition 37.0 parts of benzoyl chloride, dissolved in 65 parts i by volume of chloroform, are added dropwise at 10 to a solution of 44.5 parts of (N-methyl-4-piperidone)- in 65 parts by volume of chloroform, the resultant solution is boiled under reflux for hour and then, after cooling the solution to 0, ice-cold aqueous caustic soda solution of 6% strength is added.

128 to 130 under a pressure of 0.003

Hydrogenation of 10.65 parts of the so-obtained benzoyl-hydrazone in 75 parts presence of 0.2 part of pre-hydrogenated platinum oxide at room temperature and under atmospheric pressure produces w-(N- methyl-piperidyl-4)-w'-isopropyl-benzoylhydrazine, which is converted by boiling under reflux for 5 hours with aqueous hydrochloric acid of 23% strength, into w- (N-methyl-piperidyl-4 -isopropyl-hyparts of the so-obtained w-(N-methyladded dropwise and while cooling with ice to a solution of 2.93 parts of diphenyl-malonyl di-chloride in 50 parts by volume of tetrahydrofurane, after which the mixture benzene-ether mixtures, piperidyl-4) razolidine which, upon recrystallization from ether petroleum ether, has a melting point of 124-125 In order to centrated, is added, methyl-piperidyll')-2-isopropyl 4,4-diphe'nyl-3,5-diketopyrazolidine hydrochloride crystallizes out. crystallization from ethanol-ether, it melts at 247-252 (decomposition). p

by volume whereupon l-(N- After re- In the same manner as that described in the preceding example, 1 (N-rnethyl-piperidyl-4)-2-isopropyl-4,4-di-nbutyl- 3,5-diketo-pyrazolidine is prepared from 2.53 parts of di-n-butyl-malonyl dichloride and 1.71 parts Ofw-(N- methyI-piperidyl-4)-o'-isopropyl-hydrazine in the presence of 2.02 parts of triethylamine. The so-obtained pyrazolidine cannot be crystallized after the chromatography, but is obtained as an oily substance which dissolves in absolute ethanol. Passing dry hydrogen chloride into such ethanolic solution produces the monohydrochloride of the free-base in the form of crystals which, after recrystallization from acetone-ether, melt at 234 236 (decomposition).

Example 9 1n the same; manner as that described in Example 7, l-QN-methyl-piperidyl-4') 2 isopropyl 4,4-dimethyl- 3,5-diketo-pyrazolidine is prepared from 1.69 parts of dimethyl m'alonyl dichloride and 1.71 parts of w-(N- methyl-piperidyl-4)-w-isopropyl-hydrazine in the presence of 2.02 parts of triethylamine. The so-obtained free base forms crystals'without a solvent, which crystals are very readily soluble inorganic solvents. A. solution thereof in absolute ethanol yields, upon introduction thereinto of dry hydrogen chloride, crystals of the monohydrochloride of the base. Upon recrystallization of this hydrochloride from acetone-ether, it has a melting point of 26l262 (decomposition).

Example 37.7 parts of aqueous methyl-hydrazine solution of 39.5 %'strength are added dropwise, while cooling, to a solution of 45.0 parts of N-isopropyl-4-piperidone in 75 parts by volume of ethanol, and the mixture is kept at 65 for one hour. After evaporation of the ethanol and a portion of the water, the residue is dissolved in the 3-fold quantity of chloroform and is dried'over sodium sulfate. After filtration and evaporating off the solvent under reduced pressure, the resultant residue is distilled in a high vacuum. There is thus obtained (N-isopropyl-4- piperidone)-methyl-hydrazone as a light yellow oil which boils at 78/1 mm. Hg.

11.86 parts of this hydrazone are beuzoylated in chloroform solution with 9.85 parts of benzoyl chloride, while cooling. (.N-isopropyll-piperidone)-1nethyl-benzoyl-hydrazone which boils at 155-158 under a pressure of 0.002 mm. Hg is thus obtained.

4.79 parts of the last-mentioned benzoyl-hydrazone in 50 parts by volume of glacial acetic acid are hydrogenated in the presence of 0.1 part of pro-hydrogenated platinum oxide at room temperature and under atmospheric pressure, thereby producing w-(N-isopropyl-piperidyl-4)-w'- methyl-benzoyl-hydrazine. Hydrolysis of the latter by boiling under reflux for 5 hours with 75 parts by volume of aqueous hydrochloric acid of 23% strength yields o-(N-isopropyl-piperidyl-4)-w-rnethyl-hydrazine dihydrochloride which, after four recrystallizations from ethanole her, melts at 247-253 with decomposition. The free base, with boiling point or '76/0.3 mm. is obtained from the dihydrochloride by treating the latter with methanolic KOH.

1.71 parts of the so-obtained w-(N-isopropyl-piperidyl- 4)-w'-methyl-hydrazine dissolved in parts by volume of tetrahydrofurane and then 2.02 parts of triethylarnine are added dropwise, while cooling with ice, to a solution of 2.93 parts of diphenyl-malonyl dichloride in 50 parts by volume of tetrahydrofurane after which the mixture is boiled under reflux for 4 hours with stirring. The resultant mixture is then allowed to cool and after dilution with ether is extracted three times with2-normal aqueoushydrochlorie acid. The hydrochloric acid'aqueous layer is rendered alkaline with concentrated aqueous caustic soda solution, and is then extracted threetimes with chloroform. The chloroform solution is dried over sodium sulfate and evaporated under reduced pressure, leaving behind an oily crude product. The latter is dissolved in 50 parts by volume of benzene and is added to a column of parts of aluminum oxide. Benzene and benzene-ether mixtures 4'11 and 1:1 elute l-(N-isopropylpiperidyl-4') 2 methyl-4,4-diphenyl-3,S-diketo-pyrazolidine which, after recrystallization from ether-petroleum ether, has a melting point of 119-120.

Toprepare the corresponding hydrochloride, dry hydrogen chloride is passed into an ethanolic solution of the free base, after which the solution is concentrated and then diluted with ether, whereupon l-(N-isopropylpiperidyll)-2-methyl-4,4-diphenyl 3,5 diketo-pyrazolidine hydrochloride crystallizes out. After recrystallization from ethanol-ether, it melts at 235-239 (with decomposition) Example 11 A solution of 1.71 parts of w-(N-isopropyl-piperidyl- 4)-w'-methyl-hydrazine in 15 parts by volume oftetra hydroturane and then 2.02 parts of triethylamine is added dropwise, whilecooling, to a solution of 2.53 parts of di-n-butyl-malonyl dichloride in 50 parts by volume of tetrahydrofurane, after which the mixture is boiled under reflux for 4" hours, with stirring. After the mixture has cooled and has been diluted with ether, it-is extracted three times with Z-normal aqueous hydrochloric acid.

The hydrochloric aqueous layer is rendered alkaline with concentrated aqueous caustic soda solution, and is then extracted three times with chloroform. The chloroform-solution is dried over sodium sulfate and evaporated under reduced pressure, leaving behind an oily crude product. The latter is dissolved in 50 parts by volume of benzene, and the solution is poured onto a column of 90 parts ofaluminum oxide. Benzene and benzene-ether mixture (4:1) elute l-'(N-isopropyl-piperidyl-4")- 2'-methyl-4,4-di-n-butyl 3,5 diketo-pyrazolidine, as an oily substance.

To prepare the corresponding hydrochloride, dry hydrogen chloride is passed into an ethanolic solution of the free base, and, after concentration of the resultant solution, ether is added thereto, whereupon l-(N-isopropyl-piperidyl-4')-2-methyl-4,4-di-n-butyl 3,5 diketopyrazolidine hydrochloride crystallizes out. After recrystallization from ethanol-ether, it melts at 237-240 (with decomposition).

. Example 12 6.45 parts of '(N-methyLpiperidyl-4)-hydrazine and 9.4 parts of diethyl rnalonic acid dimethyl ester are added to a solution of2.3 parts of sodium in 50 parts by volume of'methanol. The methanol is then distilled oft under atmospheric pressure, and the remaining residue is heated for two-hours to under a reflux condenser. The obtained solid reaction mixture is dissolved in 500 parts by volume of ethanol, and the solution'is filtered from a small quantity of undissolved matter. Excess solid carbon dioxide is added to the clear filtrate, the precipitated salts filtered 011, and the filtrate evaporated to dryness under reduced pressure. There remains a semi-crystalline residue from which, by fractional crystallization from ethanol and acetone, there is isolated pure 1-(N-methyl-piperidyl-4' 4,4-diethyl-3,S-diketo-pyrazolidine; melting point=l86.5.

Example 13 by volume of ethanohand the solution isfiltered from a small quantity of undissolved matter. Excess solid,

cipitated salts filtered off, and the filtrate evaporated to There remains behind 1-(N-methyl-piperidyl-4')-4,4 dimethyl 3,5 diketo-pyrazolidine; melting point=262266 (with decomposition) Example 14 parts of diethyl-rnalonyl dichloride are added dropwith stirring and while hydrate and then thoroughly pressed. The so-obtained recovered, after recrystallization from absolute ethanol, in the form of platelets which, upon rapid heating to about 140, melt'with evolution of hydrazine. Upon slow heating, they melt at 255-265.

While stirring and cooling with ice, a solution of 3.45 parts of sodium nltrlte in 10 A solution of 3.2 parts of N-methyl-piperidyl-4-hy parts by volume of ether is then added Example 15 12.90 parts of N-methyl-piperidyl-4-hydrazine and 13.0 of dimethyl-malonic acid diamide are introduced of 4.6 parts of sodium in 100 parts by The ethanol is then disand the filtrate is evaporated Fractional crystallization of the so-obtained residue from methanol-ether yields pure l-(N-methylpiperidyl 4')-4,4-dimethyl-3,S-diketo-pyrazolidine which melts 'at 262-266 (decomposition).

Example 16 V 12.90 parts of N-methyl-piperidyl-4-hydrazine and 17.5 parts of diethyl-malonic acid ethylester amide are introduced into a parts by volume of absolute ethanol. then distilled The ethanol is off under atmospheric pressure, and the remaining residue is heated for flux condenser Fractional crystalremaining residue from ethanol-acetone yields the pure l-(N-methyl-piperidyl-4')-4,4-diethyl-3,5- diketopyrazolidine which melts at 186.$-190.

Having thus disclosed the invention, what is claimed is:

1. A member selected from the group consisting of 3,5-diketo-pyrazolidines which correspond to the formula 3. l (N-methyl-piperidyl-4')-4,4-diethyl 3,5 diketopyrazolidine.

4. l (N-methyl-piperidyll)-2-isopropyl-4,4-diphenyl- 3,5'-diketo-pyrazolidine.

5. l- N-methyl-piperidylA') -2-isopropyl-4,4-di-n-butyl- 3,5-diketo-pyrazolidine.

6. l (N-methyl-piperidyl-4')-4,4-dimethyl-3,5-diketopyrazolidine. v

7. A 3,5-diketo-pyrazolidine of the formula wherein each alkyl group contains 1 to 4 carbon atoms.

8. A 3,5-diketopyrazolidine of the formula N ail-ryl wherein each alkyl group contains 1 to 4 carbon atoms,

is evaporated 9. 3g-S-diketo-pyrazoiidine 10'. A 3,5-diket0- pyrazo1idine of :the' formula oftheior-mula- 'ph nyl Mk?! phenyl- O- C=O 'Alkyl-C-(|)=0, 5

: NH: \N/

N." lkyl whereinr the. alkyl" group contains 1'. to :4 carbon atoms; 11 atoms. 15 'No references cited. 7

wherein each alkyl group contains 1 to 4 carbo UNITED STATES PATENT OFFICE Certificate of Correction Patent N 0. 2,865,922 December 23, 1958 Ernst J uoker et a1.

It is hereby certified that error appears in the printed specification of theabove numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 1, lines 46 to 49, Formula (III) should appear as shown below instead of as in the patent:

R1 COX column 2, line 55, for benxoy1- read benzoy1- Signed and sealed this 23rd day of June 1959.

Attest r KARL H. AXLINE, ROBERT C. WATSON, Attestz'ng Ofieer. Oomnz'ssz'oner of Patents. 

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF 3,5-DIKETO-PYRAZOLIDINES WHICH CORRESPOND TO THE FORMULA 